This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Obesity represents a major risk factor for diseases such as type 2 diabetes, cardiovascular disease and certain types of cancer. The hypothalamus in the brain is the central regulator of food intake and thus is a key target for anti-obesity drugs. Ghrelin is a peripheral hormone that acts on hypothalamic neurons to increase food intake. Human studies have shown that infusing ghrelin increases food intake and decreases energy expenditure. However, no human studies have been undertaken to test whether a ghrelin antagonist will have the opposite effects i.e. will decrease food intake. This proposal will evaluate the effectiveness of ghrelin antagonist in decreasing appetite and adiposity and improving insulin sensitivity.